USP15 regulates p66Shc stability associated with Drp1 activation in liver ischemia/reperfusion
Abstract Liver ischemia/reperfusion (I/R) injury is a major clinical concern of liver transplantation, which accounts for organ rejection and liver dysfunction. The adaptor protein p66Shc acts as a crucial redox enzyme and is implicated in liver I/R. Elevated p66Shc expression is associated with hep...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2022-09-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-022-05277-8 |
| _version_ | 1811201373837983744 |
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| author | Xinyao Tian Yan Zhao Zhe Yang Qianrang Lu Lin Zhou Shusen Zheng |
| author_facet | Xinyao Tian Yan Zhao Zhe Yang Qianrang Lu Lin Zhou Shusen Zheng |
| author_sort | Xinyao Tian |
| collection | DOAJ |
| description | Abstract Liver ischemia/reperfusion (I/R) injury is a major clinical concern of liver transplantation, which accounts for organ rejection and liver dysfunction. The adaptor protein p66Shc acts as a crucial redox enzyme and is implicated in liver I/R. Elevated p66Shc expression is associated with hepatocellular apoptosis in liver I/R, but the molecular mechanisms of p66Shc responsible for its aberrant expression and function remain unknown. In the present study, hepatocyte-specific p66Shc-knockdown mice exhibited clear inhibition in hepatocellular apoptosis and oxidative stress under liver I/R, while hepatocyte-specific p66Shc overexpression mice displayed the deteriorative impairment. Mechanistically, p66Shc-triggered mitochondrial fission and apoptosis in liver I/R by mediating ROS-driven Drp1 activation. Furthermore, a screening for p66Shc-interacting proteins identified ubiquitin-specific protease 15 (USP15) as a mediator critical for abnormal p66Shc expression. Specifically, USP15 interacted with the SH2 domain of p66Shc and maintained its stabilization by removing ubiquitin. In vivo, p66Shc knockdown abrogated USP15-driven hepatocellular apoptosis, whereas p66Shc overexpression counteracted the antiapoptotic effect of USP15 silencing in response to liver I/R. There was clinical evidence for the positive association between p66Shc and USP15 in patients undergoing liver transplantation. In summary, p66Shc contributes to mitochondrial fission and apoptosis associated with Drp1 activation, and abnormal p66Shc expression relies on the activity of USP15 deubiquitination under liver I/R. The current study sheds new light on the molecular mechanism of p66Shc, and identifies USP15 as a novel mediator of p66Shc to facilitate better therapeutics against liver I/R. |
| first_indexed | 2024-04-12T02:19:43Z |
| format | Article |
| id | doaj.art-216ddbd8a8b24f1bbe2698173e6e3752 |
| institution | Directory Open Access Journal |
| issn | 2041-4889 |
| language | English |
| last_indexed | 2024-04-12T02:19:43Z |
| publishDate | 2022-09-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj.art-216ddbd8a8b24f1bbe2698173e6e37522022-12-22T03:52:08ZengNature Publishing GroupCell Death and Disease2041-48892022-09-0113911310.1038/s41419-022-05277-8USP15 regulates p66Shc stability associated with Drp1 activation in liver ischemia/reperfusionXinyao Tian0Yan Zhao1Zhe Yang2Qianrang Lu3Lin Zhou4Shusen Zheng5Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of MedicineDepartment of Pharmacology, Dalian Medical UniversityDepartment of Hepatobiliary and Pancreatic Surgery, Department of Liver Transplantation, Shulan (Hangzhou) HospitalDivision of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of MedicineDivision of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of MedicineDivision of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of MedicineAbstract Liver ischemia/reperfusion (I/R) injury is a major clinical concern of liver transplantation, which accounts for organ rejection and liver dysfunction. The adaptor protein p66Shc acts as a crucial redox enzyme and is implicated in liver I/R. Elevated p66Shc expression is associated with hepatocellular apoptosis in liver I/R, but the molecular mechanisms of p66Shc responsible for its aberrant expression and function remain unknown. In the present study, hepatocyte-specific p66Shc-knockdown mice exhibited clear inhibition in hepatocellular apoptosis and oxidative stress under liver I/R, while hepatocyte-specific p66Shc overexpression mice displayed the deteriorative impairment. Mechanistically, p66Shc-triggered mitochondrial fission and apoptosis in liver I/R by mediating ROS-driven Drp1 activation. Furthermore, a screening for p66Shc-interacting proteins identified ubiquitin-specific protease 15 (USP15) as a mediator critical for abnormal p66Shc expression. Specifically, USP15 interacted with the SH2 domain of p66Shc and maintained its stabilization by removing ubiquitin. In vivo, p66Shc knockdown abrogated USP15-driven hepatocellular apoptosis, whereas p66Shc overexpression counteracted the antiapoptotic effect of USP15 silencing in response to liver I/R. There was clinical evidence for the positive association between p66Shc and USP15 in patients undergoing liver transplantation. In summary, p66Shc contributes to mitochondrial fission and apoptosis associated with Drp1 activation, and abnormal p66Shc expression relies on the activity of USP15 deubiquitination under liver I/R. The current study sheds new light on the molecular mechanism of p66Shc, and identifies USP15 as a novel mediator of p66Shc to facilitate better therapeutics against liver I/R.https://doi.org/10.1038/s41419-022-05277-8 |
| spellingShingle | Xinyao Tian Yan Zhao Zhe Yang Qianrang Lu Lin Zhou Shusen Zheng USP15 regulates p66Shc stability associated with Drp1 activation in liver ischemia/reperfusion Cell Death and Disease |
| title | USP15 regulates p66Shc stability associated with Drp1 activation in liver ischemia/reperfusion |
| title_full | USP15 regulates p66Shc stability associated with Drp1 activation in liver ischemia/reperfusion |
| title_fullStr | USP15 regulates p66Shc stability associated with Drp1 activation in liver ischemia/reperfusion |
| title_full_unstemmed | USP15 regulates p66Shc stability associated with Drp1 activation in liver ischemia/reperfusion |
| title_short | USP15 regulates p66Shc stability associated with Drp1 activation in liver ischemia/reperfusion |
| title_sort | usp15 regulates p66shc stability associated with drp1 activation in liver ischemia reperfusion |
| url | https://doi.org/10.1038/s41419-022-05277-8 |
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